2-47403201-C-T

Position:

• chr2-47403201-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000251.3(MSH2):​c.10C>T​(p.Gln4Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000692 in 1,444,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q4Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 6.99

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1380 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.10C>T	p.Gln4Ter	stop_gained	1/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.10C>T	p.Gln4Ter	stop_gained	1/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444196 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 26, 2023

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 24, 2023

Variant summary: MSH2 c.10C>T (p.Gln4X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The next downstream in-frame ATG start site is at codon 26. Other truncating variants downstream of the c.10C>T nonsense variant but upstream of the potential new start codon have been classified as pathogenic in our laboratory, ClinVar, and HGMD. However, studies in patients with start-loss variants and functional studies involving a truncated Msh2 variant lacking the first 25 amino acids suggest that Msh2 proteins utilizing an alternative downstream start codon retain functional, albeit reduced, activity (e.g., Farrington_1998, Kets_2009, Cyr_2012). The variant was absent in 218968 control chromosomes. c.10C>T has been reported in the literature in individuals affected with breast cancer and esophageal squamous cell carcinoma, however without strong evidence for causality (e.g., Sun_2017, Ko_2020, Hu_2022). These reports therefore do not provide conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact of the variant on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 12, 2023

This sequence change creates a premature translational stop signal (p.Gln4*) in the MSH2 gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 26 has the potential to rescue this variant. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and/or esophageal cancer (PMID: 28724667, 31396961, 35449176). ClinVar contains an entry for this variant (Variation ID: 578361). Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2023

The p.Q4* variant (also known as c.10C>T), located in coding exon 1 of the MSH2 gene, results from a C to T substitution at nucleotide position 10. This changes the amino acid from a glutamine to a stop codon within coding exon 1. The predicted stop codon occurs within the first 150 nucleotides of the MSH2 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation through use of a downstream, in-frame AUG at codon 26 (Farrington SM et al. Am J Hum Genet, 1998 Sep;63:749-59; Kets CM et al. Eur J Hum Genet, 2009 Feb;17:159-64; Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown; however, MutS alpha complexes formed using recombinantly expressed wild type MSH6 and MSH2 with a deletion of the first 25 amino acids of the protein, demonstrated partially retained function in several biochemical assays that measured ATP binding, ATPase activity, mismatch binding, and sliding clamp formation (Cyr JL et al. Mol Carcinog, 2012 Aug;51:647-58). This alteration has been identified in multiple individuals diagnosed with breast cancer (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Hu L et al. NPJ Breast Cancer, 2022 Apr;8:52). This variant was also identified in 1/2121 samples from a cohort of Chinese patients diagnosed with esophageal squamous cell carcinoma (Ko JM et al. Int J Cancer, 2020 02;146:1042-1051). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.76
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878853797; hg19: chr2-47630340; COSMIC: COSV51878319;